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Patients can experience thrombocytopenia, anasarca, reticulin fibrosis, renal dysfunction, organomegaly, and normal immunoglobulin levels, \u2013 iMCD\u2010TAFRO. Others experience thrombocytosis, milder effusions, and hypergammaglobulinemia, \u2013iMCD\u2010Not Otherwise Specified (iMCD\u2010NOS). Though the etiology is unknown in both subtypes, iMCD symptoms and disease progression are believed to be driven by a cytokine storm, often including interleukin\u20106 (IL\u20106). However, approximately two\u2010thirds of patients do not respond to anti\u2010IL\u20106 therapy; alternative drivers and signaling pathways are not known for anti\u2010IL\u20106 nonresponders. To identify potential mediators of iMCD pathogenesis, we quantified 1129 proteins in 13 plasma samples from six iMCD patients during flare and remission. The acute phase reactant NPS\u2010PLA2 was the only significantly increased protein (<jats:italic>P<\/jats:italic>\u2009=\u2009.017); chemokines and complement were significantly enriched pathways. Chemokines represented the greatest proportion of upregulated cytokines, suggesting that iMCD involves a chemokine storm. The chemokine CXCL13, which is essential in homing B cells to germinal centers, was the most upregulated cytokine across all patients (log2 fold\u2010change\u2009=\u20093.22). Expression of CXCL13 was also significantly increased in iMCD lymph node germinal centers compared to controls in a stromal meshwork pattern. We observed distinct proteomic profiles between the two iMCD\u2010TAFRO patients, who both failed anti\u2010IL\u20106\u2010therapy, and the four iMCD\u2010NOS patients, in whom all three treated with anti\u2010IL\u20106\u2010therapy responded, suggesting that differing mechanisms may exist. This study reveals proteomic differences between flare and remission and the potential to molecularly define iMCD subgroups.<\/jats:p>","DOI":"10.1002\/ajh.25123","type":"journal-article","created":{"date-parts":[[2018,4,20]],"date-time":"2018-04-20T08:34:50Z","timestamp":1524213290000},"page":"902-912","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":90,"title":["Plasma proteomics identifies a \u2018chemokine storm\u2019 in idiopathic multicentric Castleman disease"],"prefix":"10.1002","volume":"93","author":[{"given":"Sheila K.","family":"Pierson","sequence":"first","affiliation":[{"name":"University of Pennsylvania Philadelphia Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron J.","family":"Stonestrom","sequence":"additional","affiliation":[{"name":"Hospital of the University of Pennsylvania Philadelphia Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dustin","family":"Shilling","sequence":"additional","affiliation":[{"name":"University of Pennsylvania Philadelphia Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason","family":"Ruth","sequence":"additional","affiliation":[{"name":"Castleman Disease Collaborative Network Boston Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher S.","family":"Nabel","sequence":"additional","affiliation":[{"name":"Castleman Disease Collaborative Network Boston Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amrit","family":"Singh","sequence":"additional","affiliation":[{"name":"University of British Columbia Vancouver Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Ren","sequence":"additional","affiliation":[{"name":"University of Pennsylvania Philadelphia Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katie","family":"Stone","sequence":"additional","affiliation":[{"name":"University of Arkansas for Medical Sciences Little Rock Arkansas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongzhe","family":"Li","sequence":"additional","affiliation":[{"name":"University of Pennsylvania Philadelphia Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frits","family":"van Rhee","sequence":"additional","affiliation":[{"name":"University of Arkansas for Medical Sciences Little Rock Arkansas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7367-8184","authenticated-orcid":false,"given":"David C.","family":"Fajgenbaum","sequence":"additional","affiliation":[{"name":"University of Pennsylvania Philadelphia Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2018,5,16]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.3109\/10428194.2014.953145"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajh.23291"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.3109\/10428194.2011.574759"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.17116\/terarkh201587764-71"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2016-10-746933"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajh.24242"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12185-016-1979-1"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.17305\/bjbms.2017.1930"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1097\/CCO.0b013e328355e0f3"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1128\/MMBR.05015-11"},{"issue":"4","key":"e_1_2_6_12_1","first-page":"13","article-title":"Pathogenic significance of interleukin\u20106 (IL\u20106\/BSF\u20102) in Castleman's disease","volume":"10","author":"Yoshizaki K","year":"1988","journal-title":"Blood."},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-15-0134"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2004-12-4602"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(14)70319-5"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep42316"},{"key":"e_1_2_6_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2352-3026(16)00006-5"},{"key":"e_1_2_6_18_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0015004"},{"key":"e_1_2_6_19_1","unstructured":"R Core Team. 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